Process for the preparation of taxane derivatives, new derivatives thus obtained and the compositions which contain them

ABSTRACT

This invention relates to a method for the preparation of taxane derivatives having the formula (I) and pharmaceutical compositions which contain the derivatives thus obtained. In formula (I), R is hydrogen or acetyl, R 1  is benzoyl or R 2  --O--CO wherein R 2  is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, phenyl or heterocyclyl and Het is a 5-membered optionally substituted aromatic heterocycle (thiophene, tiazole, furan, pyrrole, imidazole, oxazole, isoxazole, pyrazole). The products of formula (I) have remarkable antitumor and antileukemia properties. ##STR1##

DESCRIPTION OF THE INVENTION

This application is a 371 of PCT/FR93/01145, dated Nov. 22, 1993.

The present invention relates to the preparation of taxane derivativesof general formula: ##STR2## to the new products thus obtained and tothe pharmaceutical compositions which contain them.

In the general formula (I), R represents a hydrogen atom or an acetylradical, R₁ represents a benzoyl radical or a radical R² --O--CO-- inwhich R₂ represents an alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, bicycloalkyl, phenyl or heterocyclyl radical, and Hetrepresents an optionally substituted aromatic heterocyclyl radicalhaving 5 members and containing one or a number of heteroatoms, whichare identical or different, chosen from nitrogen, oxygen and sulphur.

More particularly, the present invention relates to the preparation ofthe products of general formula (I) in which:

R represents a hydrogen atom or an acetyl radical, R₁ represents abenzoyl radical or a radical R₂ --O--CO in which R² represents:

a straight or branched alkyl radical containing 1 to 8 carbon atoms, analkenyl radical containing 2 to 8 carbon atoms, an alkynyl radicalcontaining 3 to 8 carbon atoms, a cycloalkyl radical containing 3 to 6carbon atoms, a cycloalkenyl radical containing 4 to 6 carbon atoms or abicycloalkyl radical containing 7 to 10 carbon atoms, these radicalsoptionally being substituted by one or a number of substituents, whichare identical or different, chosen from the halogen atoms and thehydroxyl radical, alkoxy radical containing 1 to 4 carbon atoms,dialkylamino radical, each alkyl part of which contains 1 to 4 carbonatoms, piperidino radical, morpholino radical, 1-piperazinyl radical(optionally substituted in the 4-position by an alkyl radical containing1 to 4 carbon atoms or by a phenylalkyl radical, the alkyl part of whichcontains 1 to 4 carbon atoms), cycloalkyl radical containing 3 to 6carbon atoms, cycloalkenyl radical containing 4 to 6 carbon atoms,phenyl radical, cyano radical, nitro radical, carboxyl radical oralkoxycarbonyl radical, the alkyl part of which contains 1 to 4 carbonatoms,

or a phenyl radical, optionally substituted by one or a number ofradicals, which are identical or different, chosen from the alkylradicals containing 1 to 4 carbon atoms or the alkoxy radicalscontaining 1 to 4 carbon atoms,

or a saturated or unsaturated nitrogen-containing heterocyclyl radicalcontaining 5 or 6 members, optionally substituted by one or a number ofalkyl radicals containing 1 to 4 carbon atoms, it being understood thatthe cycloalkyl, cycloalkenyl or bicycloalkyl radicals may optionally besubstituted by one or a number of alkyl radicals containing 1 to 4carbon atoms, and

Het represents an aromatic heterocyclic radical having 5 members andcontaining one or a number of atoms, which are identical or different,chosen from the nitrogen, oxygen or sulphur atoms, such as thiophene,thiazole, furan, pyrrole, imidazole, isoxazole or pyrazole, optionallysubstituted by one or a number of substituents, which are identical ordifferent, chosen from the halogen atoms (fluorine, chlorine) and thealkyl, containing 1 to 4 carbon atoms, aryl, containing 6 to 10 carbonatoms, alkoxy, containing 1 to 4 carbon atoms, aryloxy, containing 6 to10 carbon atoms, amino, alkylamino, containing 1 to 4 carbon atoms,dialkylamino, each alkyl part of which contains 1 to 4 carbon atoms,acylamino, the acyl part of which contains 1 to 4 carbon atoms,alkoxycarbonylamino, containing 1 to 4 carbon atoms, acyl, containing 1to 4 carbon atoms, arylcarbonyl, the aryl part of which contains 6 to 10carbon atoms, cyano, nitro, hydroxyl, carboxyl, carbamoyl,alkylcarbamoyl, the alkyl part of which contains 1 to 4 carbon atoms,dialkylcarbamoyl, each alkyl part of which contains 1 to 4 carbon atoms,or alkoxycarbonyl, the alkoxy part of which contains 1 to 4 carbonatoms, radicals.

The preparation of the products of general formula (I) in which Rrepresents a hydrogen atom or an acetyl radical, R₁ represents a benzoylradical or a radical R₂ --O--CO-- in which R² represents a t-butylradical and Het represents a 2- or 3-thienyl or 2- or 3-furyl radical isvery particularly advantageous.

According to the present invention, the derivatives of general formula(I) can be obtained from a product of general formula: ##STR3## in whichHet and R₁ are defined as above, G₁ represents 4 a protective group ofthe hydroxyl functional group and G₂ represents an acetyl radical or aprotective group of the hydroxyl functional group, and R₃ and R₄, whichare identical or different, represent a hyrogen atom or an alkyl radicalcontaining 1 to 4 carbon atoms, or an aralkyl radical, the alkyl part ofwhich contains 1 to 4 carbon atoms and the aryl part preferablyrepresents a phenyl radical optionally substituted by one or a number ofalkoxy radicals containing 1 to 4 carbon atoms, or an aryl radicalpreferably representing a phenyl radical optionally substituted by oneor a number of alkoxy radicals containing 1 to 4 carbon atoms, or elseR₃ represents an alkoxy radical containing 1 to 4 carbon atoms or atrihalomethyl radical such as trichloromethyl or a phenyl radicalsubstituted by a trihalomethyl radical such as trichloromethyl and R₄represents a hydrogen atom, or else R₃ and R⁴ form, together with thecarbon atom to which they are bonded, a ring having 4 to 7 members, thereaction being carried out, depending on the meanings of R³ and R₄, inthe following way:

1) when R³ represents a hydrogen atom or an alkoxy radical or anoptionally substituted aryl radical and R₄ represents a hydrogen atom,the product of general formula (II) is treated in acid medium to producea product of general formula: ##STR4## in which Het and R₁ are definedas above, G'₁ represents a hydrogen atom or a protective group of thehydroxyl functional group and G'₂ represents a hydrogen atom or anacetyl radical or a protective group of the hydroxyl functional group,the G'₁ and G'₂ protective groups of which are, if necessary, replacedby hydrogen atoms to produce a product of general formula (I).

The deprotection of the side chain of the product of general formula(II) can be carried out in the presence of an inorganic acid(hydrochloric acid, sulphuric acid) or organic acid (acetic acid,methanesulphonic acid, trifluoromethanesulphonic acid,p-toluenesulphonic acid), used alone or as a mixture, the reaction beingcarried out in an organic solvent chosen from alcohols (methanol,ethanol, isopropanol), ethers (tetrahydrofuran, diisopropyl ether,methyl t-butyl ether), esters (ethyl acetate, isopropyl acetate, n-butylacetate), aliphatic hydrocarbons (pentane, hexane, heptane), halogenatedaliphatic hydrocarbons (dichloromethane, 1,2-dichloroethane), aromatichydrocarbons (benzene, toluene, xylenes) and nitriles (acetonitrile) ata temperature between -10° and 60° C., preferably between 15° and 30° C.The inorganic acid can be used in a catalytic or stoichiometric amountor in excess.

The deprotection can also be carried out under oxidizing conditions byusing, for example, cerium (IV) ammonium nitrate in anacetonitrile/water mixture or 2,3-dichloro-5,6-dicyano-1,4-benzoquinonein water.

The deprotection can also be carried out under reducing conditions, forexample by hydrogenolysis in the presence of a catalyst.

The G₁ and G₂, and G'₁ and G'₂, radicals, when they represent aprotective group of the hydroxyl functional group, are preferably2,2,2-trichloroethoxycarbonyl or 2-(2-(trichloromethyl)propoxy)carbonylradicals or trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl ortriarylsilyl radicals in which the alkyl parts contain 1 to 4 carbonatoms and the aryl parts are preferably phenyl radicals.

When, in the general formula (II), the G₁ and optionally G₂ protectivegroups represent a silylated radical, their replacement by hydrogenatoms is carried out simultaneously with the deprotection of the sidechain.

The replacement by hydrogen atoms, in the product of general formula(III), of the protective groups G'₁ and G'₂ representing a2,2,2-trichloroethoxycarbonyl or 2-(2-(trichloromethyl)propoxy)carbonylradical is carried out with zinc, optionally in combination with copper,in the presence of acetic acid at a temperature between 20° and 60° C.or by means of an inorganic or organic acid such as hydrochloric acid oracetic acid in solution in an aliphatic alcohol containing 1 to 3 carbonatoms or in an aliphatic ester such as ethyl acetate, isopropyl acetateor n-butyl acetate in the presence of zinc, optionally in combinationwith copper,

2) when R₃ and R₄, which are identical or different, represent an alkylradical containing 1 to 4 carbon atoms, or an aralkyl radical, in whichthe alkyl part contains 1 to 4 carbon atoms and the aryl part ispreferably an optionally substituted phenyl radical, or an aryl radical,preferably an optionally substituted phenyl radical, or else R³represents a trihalomethyl radical or a phenyl radical substituted by atrihalomethyl radical and R⁴ represents a hydrogen atom, or else R₃ andR₄ form, together with the carbon atom to which they are bonded, a ringhaving 4 to 7 members, the product of general formula (II) is convertedto the product of general formula: ##STR5## in which Het is defined asabove, G'₁ represents a hydrogen atom or a protective group of thehydroxyl functional group and G'₂ represents a hydrogen atom or anacetyl radical or a protective group of the hydroxyl functional group,which is acylated by means of benzoyl chloride or of a reactivederivative of general formula:

    R.sub.2 --O--CO--X                                         (V)

in which R² is defined as above and X represents a halogen (fluorine,chlorine) atom or an --O--R₂ or --O--CO--O--R² residue, to produce aproduct of general formula (III), the G'₁ and optionally G'₂ protectivegroups of which are replaced, if necessary, by hydrogen atoms to producea product of general formula (I).

The products of general formula (IV), in which G'₁ represents aprotective group of the hydroxyl functional group chosen from the2,2,2-trichloroethoxycarbonyl and 2-(2-(trichloromethyl)propoxy)carbonylradicals and G'₂ represents an acetyl radical or a protective group ofthe hydroxyl functional group chosen from the2,2,2-trichloroethoxycarbonyl and 2-(2-(trichloromethyl)propoxy)carbonylradicals, can be obtained by treating a product of general formula (II),in which Het, R₁, G₁ and G₂ are defined as above, R₃ and R₄, which areidentical or different, represent an alkyl, aralkyl or aryl radical, orelse R³ and R⁴ form, together with the carbon atom to which they arebonded, a ring having 4 to 7 members, with an inorganic acid(hydrochloric acid, sulphuric acid) or organic acid (formic acid)optionally in an alcohol containing 1 to 3 carbon atoms (methanol,ethanol, ispropanol) at a temperature between 0° and 50° C. Formic acidat a temperature in the region of 20° C. is preferably used.

The products of general formula (IV), in which G'₁ represents a hydrogenatom and G'₂ represents an acetyl radical, can be obtained by treating aproduct of general formula (II), in which G₁ represents a silylatedradical and G₂ represents an acetyl radical, R₃ and R₄, which areidentical or different, represent an alkyl, aralkyl or aryl radical, orelse R₃ and R₄ form, together with the carbon atom to which they arebonded, a ring having 4 to 7 members, with an inorganic acid(hydrochloric acid, sulphuric acid, hydrofluoric acid) or organic acid(formic acid, acetic acid, methanesulphonic acid,trifluoromethanesulphonic acid, p-toluenesulphonic acid), used alone oras a mixture, the reaction being carried out in an organic solventchosen from alcohols, ethers, esters, aliphatic hydrocarbons,halogenated aliphatic hydrocarbons, aromatic hydrocarbons or nitriles ata temperature between -10° and 60° C.

The products of general formula (IV) in which G'₁ represents a hydrogenatom and G'₂ represents a hydrogen atom or an acetyl radical can beobtained by treating a product of general formula (II), in which G₁represents a protective group chosen from the2,2,2-trichloroethoxycarbonyl or 2-(2-(trichloromethyl)propoxy)carbonylradicals, G₂ represents an acetyl radical or a protective group chosenfrom the 2,2,2-trichloroethoxycarbonyl or2-(2-(trichloromethyl)propoxy)carbonyl radicals, R₃ represents atrihalomethyl radical or phenyl radical substituted by a trihalomethylradical and R₄ represents a hydrogen atom, with zinc, optionally incombination with copper, in the presence of acetic acid at a temperaturebetween 30° and 60° C. or by means of an inorganic or organic acid suchas hydrochloric acid or acetic acid in solution in an aliphatic alcoholcontaining 1 to 3 carbon atoms (methanol, ethanol, propanol,isopropanol) or in an aliphatic ester (ethyl acetate, isopropyl acetateor n-butyl acetate) in the presence of zinc, optionally in combinationwith some copper.

The acylation of the product of general formula (IV) by means of benzoylchloride or of a reactive derivative of general formula (V) is carriedout in an inert organic solvent chosen from esters such as ethylacetate, sopropyl acetate or n-butyl acetate and halogenated aliphatichydrocarbons such as dichloromethane or 1,2-dichloroethane in thepresence of an inorganic base such as sodium bicarbonate or of anorganic base such as triethylamine. The reaction is carried out at atemperature between 0° and 50° C., preferably in the region of 20° C.

The optional replacement by hydrogen atoms of the G'₁ and G'₂ protectivegroups of the product of general formula (III), when they represent a2,2,2-trichloroethoxycarbonyl or 2-(2-(trichloromethyl)propoxy)carbonylradical, is generally carried out by treatment with zinc, optionally incombination with copper, in the presence of acetic acid at a temperaturebetween 30° and 60° C. or by means of an inorganic or organic acid suchas hydrochloric acid or acetic acid in solution in an aliphatic alcoholcontaining 1 to 3 carbon atoms (methanol, ethanol, isopropanol) or in analiphatic ester (ethyl acetate, isopropyl acetate, n-butyl acetate) inthe presence of zinc, optionally in combination with copper.

The products of general formula (II) can be obtained by esterificationof protected 10-deacetylbaccatin III or baccatin III of general formula:##STR6## in which G₁ and G₂ are defined as above, by means of an acid ofgeneral formula: ##STR7## in which Het, R₁, R₃ and R₄ are defined asabove, or of a derivative of this acid.

The esterification by means of an acid of general formula (VII) can becarried out in the presence of a condensation agent (carbodiimide,reactive carbonate) and of an activating agent (aminopyridine) in anorganic solvent (ether, ester, ketones, nitriles, aliphatichydrocarbons, halogenated aliphatic hydrocarbons, aromatic hydrocarbons)at a temperature between -10° and 90° C.

The esterification can also be carried out by using the acid of generalformula (VII) in the anhydride form, the reaction being carried out inthe presence of an activating agent (aminopyridine) in an organicsolvent (ethers, esters, ketones, nitriles, aliphatic hydrocarbons,halogenated aliphatic hydrocarbons, aromatic hydrocarbons) at atemperature between 0° and 90° C.

The esterification can also be carried out by using the acid of generalformula (VII) in the halide form or in the form of an anhydride with analiphatic or aromatic acid, optionally prepared in situ, in the presenceof a base (tertiary aliphatic amine), the reaction being carried out inan organic solvent (ethers, esters, ketones, nitriles, aliphatichydrocarbons, halogenated aliphatic hydrocarbons, aromatic hydrocarbons)at a temperature between 0° and 80° C.

The acid of general formula (VII) can be obtained by saponification ofan ester of general formula: ##STR8## in which Het, R₁, R₃ and R₄ are asdefined as above and R₅ represents an alkyl radical containing 1 to 4carbon atoms, optionally substituted by a phenyl radical.

Generally, the saponification is carried out by means of an inorganicbase (alkali metal hydroxide, carbonate or bicarbonate) in water/alcoholmedium (methanol/water) at a temperature between 10° and 40° C.

The ester of general formula (VIII) can be obtained by reacting aproduct of general formula: ##STR9## in which R₃ and R⁴ are as definedabove, in the form of a dialkyl acetal or of an enol alkyl ether, withan ester of general formula: ##STR10## in which Het, R₁ and R₅ aredefined as above, the reaction being carried out in an inert organicsolvent (aromatic hydrocarbon) in the presence of a strong inorganicacid (sulphuric acid) or strong organic acid (p-toluenesulphonic acid,optionally in the form of the pyridinium salt) at a temperature between0° C. and the boiling temperature of the reaction mixture.

The ester of general formula (X) can be obtained by reacting a productof general formula (V) with an ester of general formula: ##STR11## inwhich Het and R_(s) are as defined above, the reaction being carried outin an organic solvent (ester, halogenated aliphatic hydrocarbon) in thepresence of an inorganic or organic base at a temperature between 0° and50° C.

The product of general formula (XI), in which Het preferably representsa sulphur-containing heterocycle, can be obtained by reduction of anazide of general formula: ##STR12## in which Het and R₅ are defined asabove, by means of hydrogen in the presence of a catalyst such aspalladium-on-charcoal, the reaction being carried out in an organicsolvent (ester).

The product of general formula (XII) can be obtained by reacting anazide such as trimethylsilyl azide in the presence of zinc chloride oralkali metal (sodium, potassium, lithium) azide in water/organic medium(water/tetrahydrofuran) at a temperature between 20° C. and the boilingtemperature of the reaction mixture with an epoxide of general formula:##STR13## in which Het and R₅ are defined as above, optionally preparedin situ.

The epoxide of general formula (XIII) can be obtained, optionally insitu, by dehydrohalogenation of a product of general formula: ##STR14##in which Het is defined as above, Hal represents a halogen atom,preferably a bromine atom, and R₆ and R₇, which are identical ordifferent, represent a hydrogen atom or an alkyl radical containing 1 to4 carbon atoms or a phenyl radical, at least one being an alkyl radicalor a phenyl radical, by means of an alkali metal alkoxide, optionallyprepared in situ, in an inert organic solvent such as tetrahydrofuran ata temperature between -80° C. and 25° C.

The product of general formula (XIV) can be obtained by reacting analdehyde of general formula:

    Het-CHO                                                    (XV)

in which Het is defined as above, with a halide of general formula:##STR15## in which Hal, R₆ and R₇ are defined as above, anionizedbeforehand.

Generally, the reaction is carried out in an inert organic solventchosen from ethers (ethyl ether) and halogenated aliphatic hydrocarbons(methylene chloride) at a temperature between -80° and 25° C., in thepresence of a tertiary amine (triethylamine) and of an enolization agent(di-n-butylboron triflate).

The product of general formula (XVI) can be obtained by reacting ahalide of a haloacetic acid, preferably the bromide of bromoacetic acid,with the corresponding oxazolidinone.

The product of general formula (XI) in which Het preferably representsan oxygen-containing heterocycle can be obtained by hydrogenolysis of aproduct of general formula: ##STR16## in which Het and R₅ are as definedabove and Ph represents an optionally substituted phenyl radical.

The hydrogenolysis is generally carried out using hydrogen in thepresence of a catalyst. More particularly, a palladium-on-charcoalcontaining 1 to 10% by weight of palladium or palladium dihydroxidecontaining 20% by weight of palladium is used as catalyst.

The hydrogenolysis is carried out in an organic solvent or in a mixtureof organic solvents. It is advantageous to carry out the reaction inacetic acid, optionally in combination with an aliphatic alcoholcontaining 1 to 4 carbon atoms, such as an acetic acid/methanol mixtureat a temperature between 20° and 80° C.

The hydrogen required for the hydrogenolysis can also be provided by acompound which releases hydrogen by chemical reaction or by thermaldecomposition (ammonium formate). It is advantageous to carry out thereaction under a hydrogen pressure between 1 and 50 bar.

The product of general formula (XVII) can be obtained by hydrolysis oralcoholysis of a product of general formula: ##STR17## in which Het andPh are defined as above. It is particularly advantageous to carry out analcoholysis using an alcohol of formula R₅ --OH in which R₅ is definedas above, the reaction being carried out in an acid medium.

The alcoholysis is preferably carried out using methanol in the presenceof a strong inorganic acid such as hydrochloric acid at a temperature inthe region of the reflux temperature of the reaction mixture.

The product of general formula (XVIII) can be obtained by saponificationof an ester of general formula: ##STR18## in which Het and Ph aredefined as above and R₈ represents an alkyl, phenylalkyl or phenylradical, followed by the separation of the 3R,4S diastereoisomer ofgeneral formula (XVIII) from the other diastereoisomers.

The saponification is generally carried out using an inorganic ororganic base such as aqueous ammonia, lithium hydroxide, sodiumhydroxide or potassium hydroxide in a suitable solvent such as amethanol/water or tetrahydrofuran/water mixture at a temperture between-10° C. and 20° C.

The separation of the 3R,4S diastereoisomer can be carried out byselective crystallization from a suitable organic solvent such as ethylacetate.

The product of general formula (XIX) can be obtained by cycloaddition ofan imine of general formula: ##STR19## in which Het and Ph are definedas above, to an acid halide of general formula: ##STR20## in which R₁ isas defined as above and Y represents a halogen atom such as a bromine orchlorine atom.

The reaction is generally carried out at a temperature between 0° and50° C. in the presence of a base chosen from tertiary aliphatic amines(triethylamine) or pyridine in an organic solvent chosen from optionallyhalogenated aliphatic hydrocarbons (methylene chloride, chloroform) andaromatic hydrocarbons (benzene, toluene, xylenes).

The product of general formula (XX) can be obtained under conditionsanalogous to those described by M. Furukawa et al., Chem. Pharm. Bull.,25 (1), 181-84 (1977).

Protected 10-deacetylbaccatin III or baccatin III of general formula(VI) can be obtained under the conditions described in European PatentsEP-0,336,840 and EP-0,336,841.

The derivatives of general formula (I) can also be obtained byesterification of protected 10-deacetylbaccatin III or baccatin III ofgeneral formula (VI) by means of an acid of general formula: ##STR21##in which Het and R₁ are defined as above and G₃ represents a protectivegroup of the hydroxyl functional group chosen from the methoxymethyl,1-ethoxyethyl, benzyloxymethyl, (β-trimethylsilyloxy)methyl,tetrahydropyranyl, 2,2,2-trichloroethoxymethyl,2,2,2-trichloroethoxycarbonyl or CH₂ -Ph radicals, in which Phrepresents a phenyl radical optionally substituted by one or a number ofatoms or radicals, which are identical or different, chosen from halogenatoms and alkyl radicals containing 1 to 4 carbon atoms or alkoxyradicals containing 1 to 4 carbon atoms, or of an activated derivativeof this acid, to produce a product of general formula: ##STR22## inwhich Het, R₁, G₁, G₂ and G₃ are defined as above, followed byreplacement of the G₁, G₂ and G₃ protective groups by hydrogen atoms toproduce a product of general formula (I).

The esterification can be carried out under the conditions describedabove for the esterification of protected 10-deacetylbaccatin III orbaccatin III of general formula (VI) by means of an acid of generalformula (VII).

The replacement of the G₁, G₂ and G₃ protective groups of the product ofgeneral formula (XXIII) by hydrogen atoms is carried out by treatmentwith zinc, optionally in combination with copper, in the presence ofacetic acid at a temperature between 30° and 60° C. or by means of aninorganic or organic acid such as hydrochloric acid or acetic acid insolution in an aliphatic alcohol containing 1 to 3 carbon atoms or analiphatic ester such as ethyl acetate, isopropyl acetate or n-butylacetate in the presence of zinc, optionally in combination with copper,when G₂, G₂ and/or G₃ represent a 2,2,2-trichloroethoxycarbonyl or2-(2-(trichloromethyl)propoxy)carbonyl radical, or by treatment in acidmedium such as, for example, hydrochloric acid in solution in analiphatic alcohol containing 1 to 3 carbon atoms (methanol, ethanol,propanol, isopropanol) or aqueous hydrofluoric acid at a temperaturebetween 0° and 40° C. when G₁, G₂ and/or G₃ represent a silylatedradical. When G₃ represents a --CH₂ --Ph group, it is necessary toreplace this protective group by a hydrogen atom by hydrogenolysis inthe presence of a catalyst, after having replaced the G₁ and G₂protective groups by hydrogen atoms under the conditions describedabove.

The acid of general formula (XXII) can be obtained by saponification ofan ester of general formula: ##STR23## in which Het, R₁, R₅ and G₃ aredefined as above.

The saponification is generally carried out using an inorganic base(alkali metal hydroxide, carbonate or bicarbonate) in water/alcoholmedium (methanol/water) at a temperature betwewen 10° and 40° C.

The ester of general formula (XXIV) can be obtained according to theusual methods for the preparation of ethers, and more particularlyaccording to the processes described by J-N. Denis et al., J. Org.Chem., 51, 46-50 (1986) from a product of general formula (X).

The products of general formula (I) obtained by the use of the processesaccording to the invention can be purified according to known methodssuch as crystallization or chromatography.

The present invention also relates to new taxane derivatives of generalformula: ##STR24## and to the pharmaceutical compositions which containthem.

In the general formula (I),

R represents a hydrogen atom or an acetyl radical,

R₁ represents a benzoyl radical or a radical R₂ --O--CO-- in which R₂represents an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,bicycloalkyl, phenyl or heterocyclyl radical, and

Het represents an optionally substituted aromatic heterocyclyl radicalhaving 5 members and containing one or a number of identical ordifferent heteroatoms chosen from nitrogen, oxygen and sulphur with theexception of Het representing a 2-furyl or 2-thienyl radical when R₁represents a benzoyl radical or when R₂ represents an alkyl radicalcontaining 1 to 6 carbon atoms, the corresponding products beingdescribed in EP-A-0,534,708.

More particularly, the present invention relates to the products ofgeneral formula (I) in which:

R represents a hydrogen atom or an acetyl radical,

R₁ represents a benzoyl radical or a radical R₂ --O--CO in which R₂represents:

a straight or branched alkyl radical containing 1 to 8 carbon atoms, analkenyl radical containing 2 to 8 carbon atoms, an alkynyl radicalcontaining 3 to 8 carbon atoms, a cycloalkyl radical containing 3 to 6carbon atoms, a cycloalkenyl radical containing 4 to 6 carbon atoms or abicycloalkyl radical containing 7 to 10 carbon atoms, these radicalsoptionally being substituted by one or a number of substituents, whichare identical or different, chosen from the halogen atoms and thehydroxyl radical, alkoxy radical containing 1 to 4 carbon atoms,dialkylamino radical, each alkyl part of which contains 1 to 4 carbonatoms, piperidino radical, morpholino radical, 1-piperazinyl radical(optionally substituted in the 4-position by an alkyl radical containing1 to 4 carbon atoms or by a phenylalkyl radical, the alkyl part of whichcontains 1 to 4 carbon atoms), cycloalkyl radical containing 3 to 6carbon atoms, cycloalkenyl radical containing 4 to 6 carbon atoms,phenyl radical, cyano radical, nitro radical, carboxyl radical oralkoxycarbonyl radical, the alkyl part of which contains 1 to 4 carbonatoms,

or a phenyl radical, optionally substituted by one or a number ofradicals, which are identical or different, chosen from the alkylradicals containing 1 to 4 carbon atoms or the alkoxy radicalscontaining 1 to 4 carbon atoms,

or a saturated or unsaturated nitrogen-containing heterocyclyl radicalcontaining 5 or 6 members, optionally substituted by one or a number ofalkyl radicals containing 1 to 4 carbon atoms, it being understood thatthe cycloalkyl, cycloalkenyl or bicycloalkyl radicals may optionally besubstituted by one or a number of alkyl radicals containing 1 to 4carbon atoms, and

Het represents an aromatic heterocyclic radical having 5 members andcontaining one or a number of atoms, which are identical or different,chosen from the nitrogen, oxygen or sulphur atoms, such as thiophene,thiazole, furan, pyrrole, imidazole, isoxazole or pyrazole, optionallysubstituted by one or a number of substituents, which are identical ordifferent, chosen from the halogen atoms (fluorine, chlorine) and thealkyl, containing 1 to 4 carbon atoms, aryl, containing 6 to 10 carbonatoms, alkoxy, containing 1 to 4 carbon atoms, aryloxy, containing 6 to10 carbon atoms, amino, alkylamino, containing 1 to 4 carbon atoms,dialkylamino, each alkyl part of which contains 1 to 4 carbon atoms,acylamino, the acyl part of which contains 1 to 4 carbon atoms,alkoxycarbonylamino, containing 1 to 4 carbon atoms, acyl, containing 1to 4 carbon atoms, arylcarbonyl, the aryl part of which contains 6 to 10carbon atoms, cyano, nitro, hydroxyl, carboxyl, carbamoyl,alkylcarbamoyl, the alkyl part of which contains 1 to 4 carbon atoms,dialkylcarbamoyl, each alkyl part of which contains 1 to 4 carbon atoms,or alkoxycarbonyl, the alkoxy part of which contains 1 to 4 carbonatoms, radicals, with the exception of Het representing a 2-furyl or2-thienyl radical when R₁ represents a benzoyl radical or when R₂represents an alkyl radical containing 1 to 6 carbon atoms.

The products of general formula (I) in which R represents a hydrogenatom or an acetyl radical, R₁ represents a benzoyl radical or a radicalR₂ --O--CO-- in which R₂ represents a t-butyl radical and Het representsa 3-thienyl or 3-furyl radical are very particularly advantageous.

The new products of general formula (I) have biological properties.

In vitro, the measurement of the biological activity is carried out ontubulin extracted from pig brain by the method of M. L. Shelanski etal., Proc. Natl. Acad. Sci. USA, 70, 765-768 (1973). The study of thedepolymerization of the microtubules to tubulin is carried out accordingto the method of G. Chauviere et al., C. R. Acad. Sci. 293, series II,501-503 (1981). In this study, the products of general formula (I) wereshown to be at least as active as taxol and Taxotere.

In vivo, the products of general formula (I) were shown to be active inmice grafted with melanoma B16 at doses between 1 and 10 mg/kgintraperitonealy, as well as on other liquid or solid tumours.

EXAMPLES

The following examples illustrate the present invention.

Example 1

0.077 g of sodium hydrogencarbonate and then dropwise, at a temperaturein the region of 20° C., a solution of 0.219 g of di-tert-butyldicarbonate in 10 cm³ of dichloromethane are added to a solution of 0.67g of4-acetoxy-2α-benzoyloxy-5α,20-epoxy-1-hydroxy-9-oxo-7β,10β-bis[(2,2,2-trichloroethoxy)carbonyloxy]-11-taxen-13α-yl(2R,3S)-3-amino-2-hydroxy-3-(3-thienyl)propionate in 10 cm³ ofdichloromethane, maintained under an argon atmosphere. The solutionobtained is stirred for 20 hours at a temperature in the region of 20°C. and then a mixture of 25 cm³ of distilled water and of 20 cm³ ofdichloromethane is added. The aqueous phase is separated by settling andthen extracted with 20 cm³ of dichloromethane. The organic phases arecombined, dried over magnesium sulphate, filtered and then concentratedto dryness under reduced pressure (2.7 kPa) at 40° C. There is obtained0.76 g of a white foam which is purified by chromatography on 40 g ofsilica (0.063-0.2 mm) contained in a column with a diameter of 2 cm[eluent: dichloromethane/methanol (99/1 by volume)], 3 cm³ fractionsbeing collected. The fractions containing only the desired product arecombined and concentrated to dryness under reduced pressure (2.7 kPa) ata temperature in the region of 40° C. There is thus obtained 0.564 g of4-acetoxy-2α-benzoyloxy-5β,20-epoxy-1-hydroxy-9-oxo-7β,10.beta.-bis[(2,2,2-trichloroethoxy)carbonyloxy]-11-taxen-13α-yl(2R,3S)-3-tert-butoxycarbonylamino-3-(3-thienyl)-2-hydroxypropionate inthe form of a white foam.

A solution of 0.564 g of4-acetoxy-2α-benzoyloxy-5β,20-epoxy-1-hydroxy-9-oxo-7β,10.beta.-bis[(2,2,2-trichloroethoxy)carbonyloxy]-11-taxen-13α-yl(2R,3S)-3-tert-butoxycarbonylamino-3-(3-thienyl)-2-hydroxypropionate ina mixture of 10 cm³ of methanol and of 10 cm³ of acetic acid is heatedwith stirring and under an argon atmosphere to a temperature in theregion of 60° C. and then 1.2 g of zinc powder are added. The reactionmixture is then stirred for 15 minutes at 60° C., then cooled to atemperature in the region of 20° C. and filtered through sintered glasscovered with Celite. The sintered glass is washed with 3 times 10 cm³ ofdichloromethane and the filtrates are combined and then concentrated todryness under reduced pressure (2.7 kPa) at a temperature in the regionof 40° C.

25 cm³ of distilled water are added to the residue and the crystallizedsolid is separated by filtration, washed with 4 times 5 cm³ of distilledwater and dried under reduced pressure (0.27 kPa) at 20° C. for 16hours. There is obtained 0.30 g of a white foam which is purified bychromatography on 40 g of silica (0.063-0.2 mm) contained in a columnwith a diameter of 2 cm [eluent: dichloromethane/methanol (97/3 byvolume)], 5 cm³ fractions being collected. The fractions which containonly the desired product are combined and concentrated to dryness underreduced pressure (0.27 kPa) at 40° C. for 16 hours. There is thusobtained 0.18 g of4-acetoxy-2α-benzoyloxy-5β,20-epoxy-1,7β,10β-trihydroxy-9-oxo-11-taxen-13α-yl(2R,3S)-3-tert-butoxycarbonylamino-3-(3-thienyl)-2-hydroxypropionate inthe form of a white foam, the characteristics of which are thefollowing:

optical rotation: [α]_(D) ²⁰ =-30° (c=0.36, methanol)

NMR spectrum: (400 MHz, CDCl₃, δ in ppm): 1.20 (s, 3H, --CH₃ 16 or 17),1.30 (s, 3H, --CH₃ 16 or 17), 1.40 (s, 9H, --C(CH₃)₃), 1.70 (s, 1H,--OH1), 1.82 (s, 3H, --CH₃ 19), 1.88 (m, 1H, --(CH)--H6), 1.95 (s, 3H,--CH₃ 18), 2.40 (m, 5H, --CH₂ --14 and --COCH₃), 2.62 (m, 1H,--(CH)--H6), 3.40 (d, 1H, --OH 2'), 4.00 (d, 1H, --H3), 4.20 (bs, 1H,--OH10), 4.25 (m, 2H, --H7 and --(CH)--H20), 4.35 (d, 1H, --(CH)--H20),4.65 (dd, 1H, --H2'), 4.97 (dd, 1H, --H5), 5.20 to 5.40 (m, 3H, --H3',--H10 and --NHCOOC(CH₃)₃), 5.75 (d, 1H, --H2), 6.25 (t, 1H, --H13), 7.15(d, 1H, 3-thienyl-(--H4)), 7.35 (bs, 1H, 3-thienyl-(--H2)), 7.40 (dd,1H, 3-thienyl-(--H5)), 7.55 (dd, 2H, --OCOC₆ H₅ (--H3 and --H5)), 7.65(t, 1H, --OCOC₆ H₅ (--H4)), 8.15 (d, 2H, --OCOC₆ H₅ (--H2 and --H6)).

4-Acetoxy-2α-benzoyloxy-5β,20-epoxy-1-hydroxy-9-oxo-7β,10.beta.-bis[(2,2,2-trichloroethoxy)carbonyloxy]-11-taxen-13α-yl(2R,35)-3-amino-2-hydroxy-3-(3-thienyl)propionate can be prepared in thefollowing way:

A solution of 0.87 g of4-acetoxy-2α-benzoyloxy-5α,20-epoxy-1-hydroxy-9-oxo -7β,10β-bis[(2,2,2-trichloroethoxy)carbonyloxy]-11-taxen-13α-yl(2RS,4S,5R)-3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4-(3-thienyl)oxazolidine-5-carboxylatein 8 cm³ of formic acid is stirred for 4 hours at a temperature in theregion of 20° C. and then concentrated to dryness under reduced pressure(2.7 kPa) at 40° C. A mixture of 100 cm³ of dichloromethane and of 15cm³ of a saturated aqueous sodium hydrogencarbonate solution is added tothe residue. The aqueous phase is separated by settling and extractedwith 15 cm³ of dichloromethane. The organic phases are combined, driedover magnesium sulphate, filtered and then concentrated to dryness underreduced pressure (2.7 kPa) at 40° There is obtained 0.73 g of a whitefoam which is purified by chromatography on 40 g of silica (0.063-0.2mm) contained in a column with a diameter of 2 cm [eluent:dichloromethane/methanol (98/2 by volume)], 5 cm³ fractions beingcollected. The fractions which contain only the desired product arecombined and concentrated to dryness under reduced pressure (2.7 kPa) ata temperature in the region of 40° C. There is thus obtained 0.455 g of4-acetoxy-2α-benzoyloxy-5β,20-epoxy-1-hydroxy-9-oxo-7β,10.beta.-bis[(2,2,2-trichloroethoxy)carbonyloxy]-11-taxen-13α-yl(2R,3S)-3-amino-2-hydroxy-3-(3-thienyl)propionate in the form of whitefoam.

4-Acetoxy-2α-benzoyloxy-5β,20-epoxy-1-hydroxy-9-oxo-7β,10.beta.-bis[(2,2,2trichloroethoxy)carbonyloxy]-11-taxen-13α-yl(2RS,4S,5R)-3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4-(3-thienyl)oxazolidine-5-carboxylatecan be prepared in the following way:

A solution of 0.45 g of(2RS,4S,5R)-3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4-(3-thienyl)oxazolidine-5-carboxylicacid and of 0.602 g of4-acetoxy-2α-benzoyloxy-5β,20-epoxy-1,13α-dihydroxy-9-oxo-7β,10β-bis[(2,2,2-trichloroethoxy)carbonyloxy]-11-taxenein 100 cm³ of toluene is dehydrated by azeotropic distillation of thetoluene at a temperature in the region of 60° C. and under a pressure of13.3 kPa. 10 cm³ of toluene are thus removed in 20 minutes. After havingcooled the reaction mixture to a temperature in the region of 20° C.,0.277 g of N,N'-dicyclohexylcarbodiimide and 0.041 g of4-dimethylaminopyridine are added. The reaction medium is then stirredfor 1 hour 30 minutes at a temperature in the region of 20° C. and thena mixture of 250 cm³ of dichloromethane and of 7 cm³ of a saturatedaqueous sodium hydrogencarbonate solution is added. The aqueous phase isseparated by settling and then extracted with 15 cm³ of dichloromethane.The organic phases are combined, dried over magnesium sulphate, filteredand then concentrated to dryness under reduced pressure (2.7 kPa) at 50°C. There are obtained 1.36 g of a white foam which is purified bychromatography on 50 g of silica (0.063-0.2 mm) contained in a columnwith a diameter of 2 cm [eluent: dichloromethane/methanol (99/1 byvolume)], 10 cm³ fractions being collected. The fractions containingonly the desired product are combined and concentrated to dryness underreduced pressure (2.7 kPa) at a temperature in the region of 40° C.There is thus obtained 0.83 g of4-acetoxy-2α-benzoyloxy-5β,20-epoxy-1-hydroxy-9-oxo-7β,10.beta.-bis[(2,2,2-trichloroethoxy)carbonyloxy]-11-taxen-13α-yl(2RS,4S,5R)-3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4-(3-thienyl)oxazolidine-5-carboxylatein the form of white foam.

4-Acetoxy-2α-benzoyloxy-5β,20-epoxy-1,13α-dihydroxy-9-oxo-7β,10β-bis[(2,2,2-trichloroethoxy)carbonyloxy]-11-taxenecan be prepared according to the method described in European PatentEP-0,336,841.

(2RS,4S,5R)-3-tert-Butoxycarbonyl-2-(4-methoxyphenyl)-4-(3-thienyl)oxazolidine-5-carboxylicacid can be prepared in the following way:

A solution of 0.4 g of lithium hydroxide hydrate in 1.5 cm³ of distilledwater is added, at a temperature in the region of 25° C., to a solutionof 1.36 g of ethyl(2RS,4S,5R)-3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4-(3-thienyl)oxazolidine-5-carboxylatein 20 cm³ of ethanol. The reaction medium is stirred for 1 hour at atemperature in the region of 25° C. and then concentrated to drynessunder reduced pressure (2.7 kPa) at a temperature in the region of 40°C. The residue obtained is dissolved in 50 cm³ of distilled water andthen extracted with 3 times 50 cm³ of diethyl ether. The aqueous phaseis then acidified to a pH in the region of 1 with a 1N aqueoushydrochloric acid solution and then extracted with 3 times 50 cm³ ofdichloromethane.

The organic phases are combined, dried over magnesium sulphate, filteredand then concentrated to dryness under reduced pressure (2.7 kPa) at atemperature in the region of 40° C. There is thus obtained i g of(2RS,4S,5R)-3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4-(3-thienyl)oxazolidine-5-carboxylicacid in the form of a white foam.

Ethyl(2RS,4S,5R)-3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4-(3-thienyl)oxazolidine-5-carboxylatecan be prepared in the following way:

A solution of 1.9 g of ethyl(2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-(3-thienyl)propionate andof 75 mg of pyridinium p-toluenesulphonate in 18 cm³ of toluene isheated to boiling and the distillate is collected in a Dean and Starkapparatus. After having removed 10 cm³ of distillate, a solution of 1.06cm³ of the dimethyl acetal of anisaldehyde in 6 cm³ of toluene is addeddropwise and reflux is maintained for 2 hours 30 minutes. The reactionmedium is cooled to a temperature in the region of 40° C. andconcentrated to dryness under reduced pressure (2.7 kPa) at atemperature in the region of 40° C. There are obtained 2.62 g of a brownoil which is purified by chromatography on 100 g of silica (0.04-0.063mm) contained in a column with a diameter of 5 cm [eluent: petroleumether/diethyl ether (80/20 by volume)], 4 cm³ fractions being collected.The fractions containing only the desired product are combined andconcentrated to dryness under reduced pressure (2.7 kPa) at atemperature in the region of 40° C. There are thus obtained 1.8 g ofethyl(2RS,4S,5R)-3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4-(3-thienyl)oxazolidine-5-carboxylatein the form of a yellow oil.

Ethyl(2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-(3-thienyl)propionate canbe prepared in the following way:

1.65 g of sodium hydrogencarbonate and then dropwise, at a temperaturein the region of 20° C., a solution of 4.7 g of di-tert-butyldicarbonate in 10 cm³ of dichloromethane are added to a solution of3.75g of ethyl (2R,3S)-3-amino-2-hydroxy-3-(3-thienyl)propionate in 100cm³ of dichloromethane, maintained under an argon atmosphere. Thesolution obtained is stirred for 72 hours at a temperature in the regionof 20° C. and then 60 cm³ of distilled water are added. The aqueousphase is separated by settling and then extracted with 3 times 50 cm³ ofdichloromethane. The organic phases are combined, dried over magnesiumsulphate, filtered and then concentrated to dryness under reducedpressure (2.7 kPa) at 40° C. There are obtained 9.15 g of a brown oilwhich is purified by chromatography on 300 g of silica (0.063-0.2 mm)contained in a column with a diameter of 5 cm [eluent: cyclohexane/ethylacetate (70/30 by volume)], 20 cm³ fractions being collected. Thefractions containing only the desired product are combined andconcentrated to dryness under reduced pressure (2.7 kPa) at atemperature in the region of 40° C. There are thus obtained 4.95 g ofethyl(2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-(3-thienyl)propionate inthe form of a colorless oil which crystallizes at room temperature.

Ethyl (2R,3S)-3-amino-2-hydroxy-3-(3-thienyl)propionate can be preparedin the following way:

0.2 g of 10% palladium-on-charcoal powder is added to a solution of 4.3g of ethyl (2R,3S)-3-azido-2-hydroxy-3-(3-thienyl)propionate in 70 cm³of ethyl acetate. The reaction mixture is stirred under a pressure of120 kPa of hydrogen and at a temperature in the region of 22° C. for 21hours and then filtered through sintered glass covered with Celite. Thesintered glass is washed with 3 times 5 cm³ of ethyl acetate and thefiltrates are combined and then concentrated to dryness under reducedpressure (2.7 kPa) at a temperature in the region of 40° C. There arethus obtained 3.75 g of ethyl (2R,3S)-3-amino-2-hydroxy-3-(3thienyl)propionate in the form of white crystals melting at 85° C.

Ethyl (2R,3S)-3-azido-2-hydroxy-3-(3-thienyl)propionate can be preparedin the following way:

9.6 cm³ of a 1.6M solution of n-butyllithium in hexane and then,dropwise, a solution of 3.1 g of(4S,SR)-(2S,3R)-3-[2-bromo-3-hydroxy-3-(3-thienyl)-1-oxopropyl]-4-methyl-5-phenyloxazolidin-2-onein 50 cm³ of tetrahydrofuran are added, while maintaining thetemperature at -75° C., to a solution, cooled to a temperature in theregion of -75° C., of 0.9 cm³ of ethanol in 15 cm³ of anhydroustetrahydrofuran. The reaction medium is reheated to a temperature in theregion of 15° C., then maintained at 15° C. for 15 minutes and recooledagain to a temperature in the region of -75° C. A solution of 2.0 g ofcitric acid in 10 cm³ of tetrahydrofuran is then added while maintainingthe temperature at -75° C. The reaction medium is reheated to atemperature in the region of -10° C. and 20 cm³ of distilled water areadded. The organic phase is separated by settling and washed with 2times 10 cm³ of a saturated sodium chloride solution.

25 cm³ of ethylene glycol monomethyl ether, 25 cm³ of distilled water,2.45 g of sodium azide and 1.0 g of ammonium chloride are successivelyadded to this organic phase. The reaction mixture is stirred at refluxfor 30 hours and then cooled to a temperature in the region of 20° C.The organic solvents are removed by concentrating under reduced pressure(2.7 kPa) at 40° C.

10 cm³ of diethyl ether are added to the residue obtained. The aqueousphase is separated by settling and extracted with 4 times 10 cm³ ofdiethyl ether. The organic phases are combined, dried over magnesiumsulphate, filtered and then concentrated to dryness under reducedpressure (2.7 kPa) at 40° C. There are obtained 2.47 g of an orange oilwhich is purified by chromatography on 100 g of silica (0.063-0.2 mm)contained in a column with a diamter of 2 cm [eluent: cyclohexane/ethylacetate (90/10 by volume)], 5 cm³ fractions being collected. Thefractions containing only the desired product are combined andconcentrated to dryness under reduced pressure (2.7 kPa) at atemperature in the region of 40° C. There are thus obtained 1.44 g ofethyl (2R,3S)-3-azido-2-hydroxy-3-(3-thienyl)propionate in the form of apale-yellow oil.

(4S,5R)-(2S,3R)-3-[2-Bromo-3-hydroxy-3-(3-thienyl)-1-oxopropyl]-4-methyl-5-phenyloxazolidin-2-onecan be prepared in the following way:

12.6 cm³ of triethylamine and then, dropwise, 70.4 cm³ of a 1M solutionof di-n-butylboron triflate in dichloromethane are added, at atemperature in the region of 20° C., to a solution of 19 g of(4S,5R)-3-(2-bromo-1-oxoethyl)-4-methyl-5-phenyloxazolidin-2-one in 300cm³ of anhydrous diethyl ether. The reaction medium is cooled to atemperature in the region of -75° C., a solution of 4.2 cm³ ofthiophene-3-carbaldehyde in 10 cm³ of diethyl ether is then added whilemaintaining the temperature at -75° C., and the reaction medium isreheated to a temperature in the region of 0° C. and maintained at 0° C.for 1 hour 30 minutes. 40 cm³ of a saturated sodium hydrogensulphatesolution are then added, the aqueous phase is separated by settling andextracted with 2 times 50 cm³ of diethyl ether. The organic phases arecombined, dried over magnesium sulphate, filtered and then concentratedto dryness under reduced pressure (2.7 kPa) at 40° There are obtained43.2 g of a brown oil which is purified by chromatography on 500 g ofsilica (0.063-0.2 mm) contained in a column with a diameter of 5 cm[eluent: cyclohexane/ethyl acetate (90/10 by volume)], 100 cm³ fractionsbeing collected. The fractions containing only the desired product arecombined and concentrated to dryness under reduced pressure (2.7 kPa) ata temperature in the region of 40° C. There are thus obtained, aftercrystallization from diisopropyl ether, 14 g of(4S,5R)-(2S,3R)-3-[2-bromo-3-hydroxy-3-(3-thienyl)-1-oxopropyl]-4-methyl-5-phenyloxazolidin-2-onemelting at 124° C.

(4S,5R)-3-(2-Bromo-1-oxoethyl)-4-methyl-5-phenyloxazolidin-2-one can beprepared under the conditions described in International Application PCTWO 92/09589.

Example 2

0.066 g of sodium hydrogencarbonate and then, dropwise, at a temperaturein the region of 20° C., a solution of 0.188 g of di-tert-butyldicarbonate in 10 cm³ of dichloromethane are added to a solution of 0.75g of4-acetoxy-2α-benzoyloxy-5β,20-epoxy-1-hydroxy-9-oxo-7β,10.beta.-bis[(2,2,2-trichloroethoxy)carbonyloxy]-11-taxen-13α-yl(2R,3S)-3-amino-2-hydroxy-3-(3-furyl)propionate in 40 cm³ ofdichloromethane, maintained under an argon atmosphere. The solutionobtained is stirred for 20 hours at a temperature in the region of 20°C. and then a mixture of 25 cm³ of distilled water and of 20 cm³ ofdichloromethane is added. The aqueous phase is separated by settling andthen extracted with 20 cm³ of dichloromethane. The organic phases arecombined, dried over magnesium sulphate, filtered and then concentratedto dryness under reduced pressure (2.7 kPa) at 40° C. There is obtained0.85 g of a white foam which is purified by chromatography on 70 g ofsilica (0.063-0.2 mm) contained in a column with a diameter of 2.5 cm[eluent: dichloromethane/methanol (99/1 by volume)], 5 cm³ fractionsbeing collected. The fractions containing only the desired product arecombined and concentrated to dryness under reduced pressure (2.7 kPa) ata temperature in the region of 40° C. There is thus obtained 0.74 g of4-acetoxy-2α-benzoyloxy-5β,20-epoxy-1-hydroxy-9-oxo-7β,10.beta.-bis[(2,2,2-trichloroethoxy)carbonyloxy]-11-taxen-13α-yl(2R,3S)-3-tert-butoxycarbonylamino-3-(3-furyl)-2-hydroxypropionate inthe form of a white foam.

A solution of 0.73 g of4-acetoxy-2α-benzoyloxy-5β,20-epoxy-1-hydroxy-9-oxo-7β,10.beta.-bis[(2,2,2-trichloroethoxy)carbonyloxy]-11-taxen-13α-yl(2R,3S)-3-tert-butoxycarbonylamino-3-(3-furyl)-2-hydroxypropionate in amixture of 15 cm³ of methanol and of 15 cm³ of acetic acid is heatedwith stirring and under an argon atmosphere to a temperature in theregion of 60° C. and then 1.5 g of zinc powder are added. The reactionmixture is then stirred for 10 minutes at 60° C., then cooled to atemperature in the region of 20° C. and filtered through sintered glasscovered with Celite. The sintered glass is washed with 3 times 10 cm³ ofmethanol and the filtrates are combined and then concentrated to drynessunder reduced pressure (2.7 kPa) at a temperature in the region of 40°C.

15 cm³ of distilled water are added to the residue and the crystallizedsolid is separated by filtration, washed with 6 times 5 cm³ of distilledwater and dried under reduced pressure (0.27 kPa) at 20° C. for 16hours. There is obtained 0.49 g of a white foam which is purified bychromatography on 40 g of silica (0.063-0.2 mm) contained in a columnwith a diameter of 2 cm [eluent: dichloromethane/methanol (97/3 byvolume)], 5 cm³ fractions being collected. The fractions containing onlythe desired product are combined and concentrated to dryness underreduced pressure (0.27 kPa) at 40° C. for 16 hours. There is thusobtained 0.31 g of4-acetoxy-2α-benzoyloxy-5β,20-epoxy-1,7β,10β-trihydroxy-9-oxo-11-taxen-13α-yl(2R,3S)-3-tert-butoxycarbonylemino -3-(3-furyl)-2-hydroxypropionate inthe form of a white foam, the characteristics of which are thefollowing:

optical rotation: [α]_(D) ²⁰ =-33° (c=0.47, methanol)

NMR spectrum: (400 MHz, CDCl₃, δ in ppm): 1.20 (s, 3H, --CH₃ 16 or 17),1.30 (s, 3H, --CH₃ 16 or 17), 1.40 (s, 9H, --C(CH₃)₃), 1.72 (s, 1H,--OH1), 1.80 (s, 3H, --CH₃ 19), 1.90 (m, 1H, --(CH)--H6), 1.92 (s, 3H,--CH₃ 18), 2.35 (m, 5H, --CH₂ --14 and --COCH₃), 2.60 (m, 1H,--(CH)--H6), 3.50 (d, 1H, --OH2'), 3.95 (d, 1H, --H3), 4.25 (m, 3H,--OH10, --(CH)--H 20 and --H7), 4.35 (d, 1H, --(CH)--H20), 4.58 (dd, 1H,--H2'), 5.00 (dd, 1H, --H5), 5.20 (m, 3H, --H3', --H10 and--NHCOOC(CH₃)₃), 5.70 (d, 1H, --H2), 6.25 (t, 1H, --H3), 6.50 (bs, 1H,3-furyl-(--H7.45 (bd, 1H, 3-furyl-(--H2)), 7.55 (m, 3H, --OCOC₆ H₅ (--H3and --H5) and 3-furyl-(--H5)), 7.65 (t, 1H, --OCOC₆ H₅ (--H4)), 8.15 (d,2H, --OCOC₆ H₅ (--H2 and --H6)).

4-Acetoxy-2α-benzoyloxy-5β,20-epoxy-1-hydroxy-9-oxo-7β,10.beta.-bis[(2,2,2-trichloroethoxy)carbonyloxy]-11-taxen-13α-yl(2R,3S)-3-amino-2-hydroxy-3-(3-furyl) propionate can be prepared in thefollowing way:

A solution of 1.15 g of 4-acetoxy-2α-benzoyloxy -5β,20-epoxy -1-hydroxy-9-oxo-7β,10β-bis[(2,2,2-trichloroethoxy)carbonyloxy]-11-taxen-13.alpha.-yl(2RS,4S,5R)-3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4-(3-furyl)oxazolidine-5-carboxylate in 20 cm³ offormic acid is stirred for 4 hours at a temperature in the region of 20°C. and then concentrated to dryness under reduced pressure (2.7 kPa) at40° C. A mixture of 100 cm³ of dichloromethane and of 25 cm³ of asaturated aqueous sodium hydrogencarbonate solution is added to theresidue. The aqueous phase is separated by settling and extracted with15 cm³ of dichloromethane. The organic phases are combined, dried overmagnesium sulphate, filtered and then concentrated to dryness underreduced pressure (2.7 kPa) at 40° C. There are obtained 1.5 g of a whitefoam which is purified by chromatography on 70 g of silica (0.063-0.2mm) contained in a column with a diameter of 2.5 cm eluent:dichloromethane/methanol (98/2 by volume), 5 cm³ fractions beingcollected. The fractions containing only the desired product arecombined and concentrated to dryness under reduced pressure (2.7 kPa) ata temperature in the region of 40° C. There is thus obtained 0.76 g of4-acetoxy-2α-benzoyloxy-5β,20-epoxy-1-hydroxy-9-oxo-7β,10β-bis[(2,2,2-trichloroethoxy)carbonyloxy]-11-taxen-13α-yl(2R,3S)-3-amino-2-hydroxy-3-(3-furyl)propionate in the form of anorangey foam.

4-Acetoxy-2α-benzoyloxy-5β,20-epoxyl-1-hydroxy-9-oxo-7β,10.beta.-bis[(2,2,2-trichloroethoxy)carbonyloxy]-11-taxen-13α-yl(2RS,4S,5R)-3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4-(3-furyl)oxazolidine-5-carboxylatecan be prepared in the following way:

A solution of 0.66 g of(2RS,4S,5R)-3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4-(3-furyl)oxazolidine-5-carboxylicacid and of 1.0 g of4-acetoxy-2α-benzoyloxy-5β,20-epoxy-1,13α-dihydroxy-9-oxo-7β,10β-bis[(2,2,2-trichloroethoxy)carbonyloxy]-11-taxenein 50 cm³ of toluene is dehydrated by azeotropic distillation of thetoluene at a temperature in the region of 60° C. and under a pressure of13.3 kPa. 10 cm³ of toluene are thus removed in 20 minutes. After havingcooled the reaction medium to a temperature in the region of 20° C.,0.450 g of N,N'-dicyclohexylcarbodiimide and 0.067 g of4-dimethylaminopyridine are added. The reaction medium is then stirredfor 2 hours 30 minutes at a temperature in the region of 20° C. and thena mixture of 250 cm³ of dichloromethane and of 25 cm³ of a saturatedaqueous sodium hydrogencarbonate solution are then added. The aqueousphase is separated by settling and then extracted with 50 cm³ ofdichloromethane. The organic phases are combined, dried over magnesiumsulphate, filtered and then concentrated to dryness under reducedpressure (2.7 kPa) at 40° C. There are obtained 3.0 g of a white foamwhich is purified by chromatography on 80 g of silica (0.063-0.2 mm)contained in a column with a diameter of 2.5 cm [eluent:dichloromethane/methanol (99.5/0.5 by volume)], 10 cm³ fractions beingcollected. The fractions containing only the desired product arecombined and concentrated to dryness under reduced pressure (2.7 kPa) ata temperature in the region of 40° C. There are thus obtained 1.15 g of4-acetoxy-2α-benzoyloxy-5β,20-epoxy-1-hydroxy-9-oxo-7β,10.beta.-bis[(2,2,2-trichloroethoxy)carbonyloxy]-11-taxen-13α-yl(2RS,4S,5R)-3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4-(3-furyl)oxazolidine-5-carboxylatein the form of a white foam.

(2RS,4S,5R)-3-tert-Butoxycarbonyl-2-(4-methoxyphenyl)-4-(3-furyl)oxazolidine-5-carboxYlicacid can be prepared in the following way:

A solution of 0.24 g of lithium hydroxide hydrate in 7 cm³ of distilledwater is added, at a temperature in the region of 25° C., to a solutionof 0.775 g of methyl(2RS,4S,5R)-3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4-(3-furyl)oxazolidine-5-carboxylatein 20 cm³ of ethanol.

The reaction medium is stirred for 15 minutes at a temperature in theregion of 25° C. and then concentrated to dryness under reduced pressure(2.7 pKa) at a temperature in the region of 40° C. The residue obtainedis dissolved in 30 cm³ of distilled water and then extracted with 3times 50 cm³ of diethyl ether. The aqueous phase is then acidified to apH in the region of 3 with a 2N aqueous hydrochloric acid solution andthen extracted with 3 times 25 cm³ of dichloromethane. The organicphases are combined, dried over magnesium sulphate, filtered and thenconcentrated to dryness under reduced pressure (2.7 kPa) at atemperature in the region of 40° C. There is thus obtained 0.690 g of(2RS,4S,5R)-3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4-(3-furyl)oxazolidine-5-carboxylicacid in the form of a white foam.

Methyl (2RS,4S,5R)-3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4-(3-furyl)oxazolidine-5-carboxylate can be prepared in the followingway:

A solution of 0.75 g of methyl(2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-(3-furyl)propionate andof 33 mg of pyridinium p-toluenesulphonate in 35 cm³ of toluene isheated to boiling and the distillate is collected in a Dean and Starkapparatus. After having removed 10 cm³ of distillate, a solution of0.446 cm³ of the dimethyl acetal of anisaldehyde in 5 cm³ of toluene isadded dropwise and reflux is maintained for 1 hour 30 minutes. Thereaction medium is cooled to a temperature in the region of 40° C. andconcentrated to dryness under reduced pressure (2.7 kPa) at atemperature in the region of 40° C. There are obtained 1.4 g of a brownoil which is purified by chromatography on 70 g of silica (0.063-0.2 mm)contained in a column with a diameter of 2.5 cm [eluent:dichloromethane/methanol (99.5/0.5 by volume)], 5 cm³ fractions beingcollected. The fractions containing only the desired product arecombined and concentrated to dryness under reduced pressure (2.7 kPa) ata temperature in the region of 40° C. There is thus obtained 0.8 g ofmethyl(2RS,4S,5R)-3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4-(3-furyl)oxazolidine-5-carboxylatein the form of a pale-yellow oil.

Methyl(2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-(3-furyl)propionate canbe prepared in the following way:

0.46 g of sodium hydrogencarbonate and then, dropwise, at a temperaturein the region of 20° C., a solution of 1.23 g of di-tert-butyldicarbonate in 5 cm³ of dichloromethane are added to a solution of 0.92g of methyl (2R,3S)-3-amino-2-hydroxy-3-(3-furyl)propionate in 30 cm³ ofdichloromethane, maintained under an argon atmosphere. The solutionobtained is stirred for 20 hours at a temperature in the region of 20°C. and then 30 cm³ of distilled water are added. The aqueous phase isseparated by settling and then extracted with 3 times 25 cm³ ofdichloromethane. The organic phases are combined, dried over magnesiumsulphate, filtered and then concentrated to dryness under reducedpressure (2.7 kPa) at 40° C. There are obtained 1.36 g of a pale-yellowoil which crystallizes at room temperature.

Methyl (2R,3S)-3-amino-2-hydroxy-3-furyl propionate can be prepared inthe following way:

A solution of 2.42 g of methyl(2R,3S)-2-hydroxy-3-[(S)-1-phenyl]ethylamino]-3-furyl propionate in amixture of 40 cm³ of methanol and 0.48 cm³ of acetic acid is added to3.0 g of a 3% dispersion of palladium in powdered activated charcoal.The reaction mixture is stirred for 1 hour at 20° C. under a pressure of120 kPa of hydrogen. The reaction mixture is then filtered throughsintered glass covered with Celite. The sintered glass is washed with 3times 15 cm³ of methanol and the filtrates are combined and thenconcentrated to dryness under reduced pressure (2.7 kPa) at atemperature in the region of 40° C. 40 cm³ of distilled water are addedto the residue and the mixture is basified to a pH in the region of 7 byaddition of a 7.5N aqueous sodium hydroxide solution and then extractedwith 4 times 100 cm³ of dichloromethane. The organic phases arecombined, dried over magnesium sulphate, filtered and then concentratedto dryness under reduced pressure (2.7 kPa) at 40° C. The brown residualoil is purified by chromatography on 60 g of silica (0.04-0.063 mm)contained in a column with a diameter of 2.5 cm [eluent: ethylacetate/methanol (99/5 by volume)]. The fractions containing only thedesired product are combined and concentrated to dryness under reducedpressure (2.7 kPa) at a temperature in the region of 40° C. There isthus obtained 0.93 g of methyl (2R,3S)-3-amino-2-hydroxy-3-furylpropionate in the form of a yellow oil.

Methyl (2R,3S)-2-hydroxy-3-[((S)-1-phenyl]ethylamino-3-furyl propionatecan be prepared in the following way:

A solution of 2.18 g of(3R,4S)-3-hydroxy-4-(3-furyl)-1-[(S)-1-phenyl]ethyl-2-azetidinone in amixture of 40 cm³ of methanol and of 4 cm³ of a 12N aqueous hydrochloricacid solution is heated at reflux (65° C.) for 16 hours, then cooled toa temperature in the region of 20° C. and concentrated to dryness underreduced pressure (2.7 kPa) at a temperature in the region of 40° C. 50cm³ of distilled water are added to the residue and the mixture isbasified to a pH in the region of 7 by addition of a 7.5N aqueous sodiumhydroxide solution and then extracted with 3 times 50 cm³ of ethylacetate. The organic phases are combined, dried over magnesium sulphate,filtered and then concentrated to dryness under reduced pressure (2.7kPa) at 40° C. There are thus obtained 2.48 g of methyl(2R,3S)-2-hydroxy-3-[((S)-1-phenyl]ethylamino-3-furyl propionate in theform of a pale-yellow oil.

(3R,4S)-3-Hydroxy-4-(3-furyl)-1-[(S)-1-phenyl]ethyl-2-azetidinone can beprepared in the following way:

A solution of 9.24 g of a mixture, in a 70/30 molar proportion, of thetwo diastereoisomers of3-acetoxy-4-(3-furyl)-1-[(S)-1-phenyl]ethyl-2-azetidinone, form A andform B, in 200 cm³ of tetrahydrofuran is added over 35 minutes, withstirring and at a temperature in the region of 0° C., to a mixture of213 cm³ of a 1N aqueous potassium hydroxide solution and of 200 cm³ oftetrahydrofuran.

On completion of the addition, the reaction medium is stirred at atemperature in the region of 0° C. for 1 hour and then 200 cm³ of asaturated aqueous sodium hydrogencarbonate solution and 200 cm³ ofdistilled water are added. The aqueous phase is separated by settlingand extracted with 3 times 200 cm³ of ethyl acetate. The organic phasesare combined, dried over magnesium sulphate, filtered and thenconcentrated to dryness under reduced pressure (2.7 kPa) at 40° C. Thereare thus obtained 8.1 g of a yellow oil which is crystallized from 100cm³ of a mixture of ethyl acetate and hexane (60/40 by volume) to give3.53 g of(3R,4S)-3-hydroxy-4-(3-furyl)-1-[(S)-1-phenyl]ethyl-2-azetidinone in theform of white crystals melting at 100° C.

The mixture, in a 70/30 molar proportion, of the two diastereoisomers of3-acetoxy-4-(3-furyl)-1-[(S)-1-phenyl]ethyl-2-azetidinone, form A andform B, can be prepared in the following way:

15.5 cm³ of triethylamine are added, with stirring and at a temperaturein the region of -15° C., and 5.0 cm³ of 2-acetoxyacetyl chloride areadded dropwise, over 75 minutes and while being maintained at thistemperature, to a solution of 11.69 g of(S)-1-phenyl-N-[3-furylidene]ethylamine in 100 cm³ of toluene. Thesolution obtained is reheated to a temperature in the region of 20° C.and maintained at this temperature, with stirring, for 16 hours and then300 cm³ of a 2.7N aqueous hydrochloric acid solution are added. Theorganic phase is separated by settling, washed with 2 times 150 cm³ ofdistilled water and then with 150 cm³ of a saturated aqueous sodiumhydrogencarbonate solution, dried over magnesium sulphate, filtered andthen concentrated to dryness under reduced pressure (2.7 kPa) at 40° C.There are thus obtained 12.8 g of a brown oil which is purified bychromatography on 400 g of silica (0.04-0.063 mm) contained in a columnwith a diameter of 5 cm [eluent: cyclohexane/ethyl acetate (80/20 byvolume)]. The fractions containing only the desired product are combinedand concentrated to dryness under reduced pressure (0.27 kPa) at 40° C.There are thus obtained 0.7 g of a mixture, in a 70/30 molar proportion,of the two diastereoisomers of3-acetoxy-4-(3-furyl)-1-[(S)-1-phenyl]ethyl-2-azetidinone, form A andform B, in the form of a yellow oil.

(S)-1-Phenyl-N-[3-furylidene]ethylamine can be prepared in the followingway:

25.4 cm³ of (S)-1-phenylethylamine and 5 g of 4 Å molecular sieve areadded, with stirring and at a temperature in the region of -15° C., to asolution of 19.22 g of furan-3-carbaldehyde in 165 cm³ ofdichloromethane. The reaction mixture is reheated to a temperature inthe region of 20° C. and maintained at this temperature, with stirring,for 24 hours and then filtered through sintered glass covered withCelite. The sintered glass is washed with 3 times 30 cm³ ofdichloromethane and the filtrates are combined and then concentrated todryness under reduced pressure (2.7 kPa) at a temperature in the regionof 40° C. There are thus obtained 39.85 g of(S)-1-phenyl-N-[3-furylidene]ethylamine in the form of a brown oil.

Example 3

A solution of 0.60 g of4-acetoxy-2α-benzoyloxy-5β,20-epoxy-1-hydroxy-9-oxo-7β,10.beta.-bis[(2,2,2-trichloroethoxy)carbonyloxy]-11-taxen-13α-yl(2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-(4-thiazolyl)propionatein a mixture of 8 cm³ of methanol and of 8 cm³ of acetic acid is heatedwith stirring and under an argon atmosphere to a temperature in theregion of 60° C. and then 1.2 g of zinc powder are added. The reactionmixture is then stirred for 15 minutes at 60° C., then cooled to atemperature in the region of 20° C. and filtered through sintered glasscovered with Celite. The sintered glass is washed with 3 times 10 cm³ ofmethanol and the filtrates are combined and then concentrated to drynessunder reduced pressure (2.7 kPa) at a temperature in the region of 40°C.

10 cm³ of distilled water are added to the residue and the crystallizedsolid is separated by filtration, washed with 4 times 5 cm³ of distilledwater and dried under reduced pressure (0.27 kPa) at 20° C. for 16hours. There is obtained 0.35 g of a white foam which is purified bychromatography on silica gel deposited on a plate (gel thickness of 0.25mm. 20×20 cm plates) in 10 mg fractions. After using U.V. radiation tolocate the region corresponding to the desired adsorbed product, thisregion is scraped off and the silica collected is washed on sinteredglass with 10 times 10 cm³ of dichloromethane and with 5 times 5 cm³ ofmethanol. The filtrates are combined and concentrated to dryness underreduced pressure (0.27 kPa) at 40° C. for 16 hours. There is thusobtained 0.135 g of4-acetoxy-2α-benzoyloxy-5β,20-epoxy-1,7β,10β-trihydroxy-9-oxo-11-taxen-13α-yl(2R,3S)-3-tert-butoxycarbonylamino-3-(4-thiazolyl)-2-hydroxypropionatein the form of a white foam, the characteristics of which are thefollowing:

optical rotation: [ ]_(D) ²⁰ =-32(c=0.57 methanol)

N.M.R spectrum: (400 MHz, CDCl₃, δ in ppm) 1.12 (s, 3H, --CH₃ 16 or 17),1.24 (s, 3H, --CH₃ 16 or 17), 1.40 (s, 9H, --C(CH₃)₃), 1.70 (s, 1H,--OH1), 1.78 (s, 3H, --CH₃ 19), 1.87 (mt, 1H, --(CH)--H6), 1.90 (s, 3H,--CH₃ 18), 2.30 (split ab, J=16 and 9 Hz, 2H, --CH₂ 14), 2.45 (s, 3H,--COCH₃), 2.60 (m,t 1H, --(CH)--H6), 3.94 (d, J=7 Hz, 1H, H3), 4.20 (d,J=8 Hz, 1H, --(CH)--H20), 4.20 (broad, 1H, --OH10), 4.25 (broad dd,J=11.5 and 7.5 Hz, 1H, --H7), 4.34 (d, J=8 Hz, 1H, --(CH)--H20), 4.88(broad s, 1H, --H2'), 4.97 (broad d, J =10 Hz, 1H, H5), 5.20 (s, 1H,--H10), 5.47 (broad d, J=10 Hz, 1H, H3'), 5.68 (d, J=10 Hz, 1H, --CONH),5.70 (d, J=7 Hz, 1H, --H2), 6,20 (t, J=9 Hz, 1H, --H13), 7.32 (broad s,1H, 4-thiazolyl-(--H5)), 7.50 (t, J=7.5 Hz, 2H, --OCOC₆ H₅ (--H3 and--H5)), 7.60 (t, J=7.5 Hz, 1H, --OCOC₆ H₅ (--H4)), 8.11 (d, J=7.5 Hz,2H, --OCOC₆ H₅ (--H2 and --H6)), 8.80 (d, J=1.5 Hz, 1H,4-thiazolyl-(--H2)).

By carrying out the reaction as in Example 2, but from suitable startingmaterials, the following intermediates are prepared:

4-acetoxy-2α-benzoyloxy-5β,20-epoxy-1-hydroxy-9-oxo-7β,10.beta.-bis[(2,2,2-trichloroethoxy)carbonyloxy]-11-taxen-13α-yl(2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-(4-thiazolyl)propionatein the form of a white foam.

4-acetoxy,2a-benzoyloxy-5β,20-epoxy-1-hydroxy-9-oxo-7β,10β-bis[(2,2,2-trichloroethoxy)carbonyloxy]-11-taxen-13α-yl(2R,3S)-3-amino-2-hydroxy-3-(4 thiazolyl)propionate in the form of awhite foam.

4-acetoxy,2α-benzoyloxy-5β,20-epoxy-1-hydroxy-9-oxo-7β,10β-bis[(2,2,2-trichloroethoxy)carbonyloxy]-11-taxen-13α-yl(2RS,4S,5R)-3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4-(4-thiazolyl)oxazolidine-5-carboxylate in the form of a white foam.

(2RS,4S,5R)-3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4-(4-thiazolyl)oxazolidine -5-carboxylic acid in the form of a white foam.

methyl(2RS,4S,5R)-3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4-(4-thiazolyl)oxazolidine-5-carboxylate in the form of a pale-yellow oil.

methyl(2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-(4-thiazolyl)propionatein the form of a white foam.

methyl (2R,3S)-3-amino-2-hydroxy-3-(4-thiazolyl)propionate in the formof a pale-yellow oil.

Methyl (2R,3S)-2-hydroxy-3-[((S)-1-phenyl]ethylamino-4-thiazolylpropionate in the form of a pale-yellow oil.

(3R,4S)-3-hydroxy-4-(4-thiazolyl)-1-[(S)-1phenyl]ethyl-2-azetidinone inthe form of a white foam.

the mixture, in the molar proportion: 70/30, of the two diastereoisomersof 3-acetoxy-4-(4-thiazolyl)-1-[(S)-1-phenyl]ethyl-1-2-azetidinone, formA and form B, in the form of a pale-yellow oil.

(S)-1-phenyl-N-[4-thiazolylidene]ethylamine in the form of a yellow oil.

thiazole-4-carbaldehyde can be prepared according to the methoddescribed by A. Dondoni et al., Synthesis, 1987, 998-1001.

(S)-1-(4-methoxyphenyl)ethylamine can be prepared according to themethod described by H.O. Bernhard et al., Helv. Chim. Acta, 1973, 56(4),1266-1303.

The new products of general formula (I) manifest significant inhibitoryactivity with respect to abnormal cell proliferation, and possesstherapeutic properties that enable patients having pathologicalconditions associated with an abnormal cell proliferation to be treated.The pathological conditions include the abnormal cell proliferation ofmalignant or nonmalignant cells of various tissues and/or organscomprising, without implied limitation, muscle, bone or connectivetissue, the skin, brain, lungs, sex organs, lymphatic or renal systems,mammary or blood cells, liver, digestive system, pancreas and thyroid oradrenal glands. These pathological conditions can also includepsoriasis, solid tumours, cancers of the ovary, breast, brain, prostate,colon, stomach, kidney or testicles, Kaposi's sarcoma,cholangiocarcinoma, choriocarcinoma, neuroblastoma, Wilms' tumour,Hodgkin's disease, melanomas, multiple myelomas, chronic lymphocyticleukaemias, and acute or chronic granulocytic lymphomas. The newproducts according to the invention are especially useful for thetreatment of cancer of the ovary. The products according to theinvention may be used to prevent or delay the appearance or reappearanceof the pathological conditions, or for treating these pathologicalconditions.

The products according to the invention may be administered to a patientaccording to different forms suited to the chosen administration route,which is preferably the parenteral route. Parenteral administrationcomprises intravenous, intraperitoneal, intramuscular or subcutaneousadministrations. Intraperitoneal or intravenous administration is moreespecially preferred.

The present invention also comprises pharmaceutical compositionscontaining at least one product of general formula (I) in a sufficientamount suitable for use in human or veterinary therapy. The compositionsmay be prepared according to the customary methods, using one or morepharmaceutically acceptable adjuvants, vehicles or excipients.Appropriate vehicles include diluents, sterile aqueous media and variousnontoxic solvents. Preferably, the compositions take the form of aqueoussuspensions or solutions, injectable solutions which can containemulsifying agents, colorants, preservatives or stabilizers.

The choice of adjuvants or excipients may be determined by thesolubility and chemical properties of the product, the particular modeof administration and good pharmaceutical practices.

For parenteral administration, sterile aqueous or nonaqueous suspensionsor solutions are used. For the preparation of nonaqueous suspensions orsolutions, natural vegetable oils such as olive oil, sesame oil orliquid paraffin, or injectable organic esters such as ethyl oleate, maybe used. The sterile aqueous solutions can consist of a solution of apharmaceutically acceptable salt dissolved in water. Aqueous solutionsare suitable for intravenous administration provided the pH isappropriately adjusted and the solution is made isotonic, for examplewith a sufficient amount of sodium chloride or glucose. Thesterilization may be carried out by heating or by any other means whichdoes not adversely affect the composition.

It is obvious that all the products participating in the compositionsaccording to the invention must be pure and nontoxic in the amountsused.

The compositions can contain at least 0.01% of therapeutically activeproduct. The amount of active product in a composition is such as toenable an appropriate dosage to be prescribed. Preferably, thecompositions are prepared in such a way that a single dose contains from0.01 to 1,000 mg approximately of active product for parenteraladministration.

The therapeutic treatment may be carried out conjointly with othertherapeutic treatments including antineoplastic medicinal products,monoclonal antibodies, immunological therapies or radiotherapies orbiological-response modifiers. The response modifiers include, withoutimplied limitation, lymphokines and cytokines such as interleukins,interferons (α, β or δ) and TNF. Other chemotherapeutic agents which areuseful in the treatment of disorders due to abnormal cell proliferationinclude, without implied limitation, alkylating agents such as nitrogenmustards, for instance mechloretamine, cyclophosphamide, melphalan andchlorambucil, alkyl sulphonates such as busulphan, nitrosoureas such ascarmustine, lomusine, semustine and streptozocin, triazenes such asdacarbazine, antimetabolites such as folic acid analogues, for instancemethotrexate, pyrimidine analogues such as fluorouracil and cytarabine,purine analogues such as mercaptopurine and thioguanine, naturalproducts such as vinca alkaloids, for instance vinblastine, vincristineand vendesine, epipodophyllotoxins such as etoposide and teniposide,antibiotics such as dactinomycin, daunorubicin, doxorubicin, bleomycin,plicamycin and mitomycin, enzymes such as L-asparaginase, various agentssuch as coordination complexes of platinum, for example cisplatin,substituted ureas such as hydroxyurea, methylhydrazine derivatives suchas procarbazine, adrenocoticoid suppressants such as mitotane andaminoglutethymide, hormones and antagonists such asadrenocorticosteroids such as prednisone, progestins such ashydroxyprogesterone caproate, methoxyprogesterone acetate and megestrolacetate, oestrogens such as diethylstilboestrol and ethinyloestradiol,antioestrogens such as tamoxifen, and androgens such as testosteronepropionate and fluoxymesterone.

The doses used for implementing the methods according to the inventionare those which permit a prophylactic treatment or a maximum therapeuticresponse. The doses vary according to the form of administration, theparticular product selected and the features distinctive to the subjectto be treated. In general, the doses are those which are therapeuticallyeffective for the treatment of disorders due to an abnormal cellproliferation. The products according to the invention may beadministered as often as necessary to obtain the desired therapeuticeffect. Some patients may respond rapidly to relatively high or lowdoses, and then require low or zero maintenance doses. Generally, lowdoses will be used at the beginning of the treatment and, if necessary,increasingly higher doses will be administered until an optimum effectis obtained. For other patients, it may be necessary to administermaintenance doses 1 to 8 times a day, preferably 1 to 4 times, accordingto the physiological requirements of the patient in question. For somepatients, it is also possible for it to be necessary to use only one totwo daily administrations.

In humans, the doses are generally between 0.01 and 200 mg/kg.Intraperitoneally, the doses will generally be between 0.1 and 100mg/kg, and preferably between 0.5 and 50 mg/kg, and still morespecifically between 1 and 10 mg/kg. Intravenously, the doses aregenerally between 0.1 and 50 mg/kg, and preferably between 0.1 and 5mg/kg, and still more specifically between 1 and 2 mg/kg. It isunderstood that, in order to choose the most suitable dosage, accountshould be taken of the administration route, the patient's weight,general state of health and age and all factors which may influence theefficacy of the treatment.

The following example illustrates a composition according to theinvention.

EXAMPLE

40 mg of the product obtained in Example 1 are dissolved in 1 cm³ ofEmulphor EL 620 and 1 cm³ of ethanol and the solution is then diluted byaddition of 18 cm³ of physiological serum.

The composition is administered via a drip for one hour by introductioninto physiological solution.

Although the invention has been described in conjunction with specificembodiments, it is evident that many alternatives and variations will beapparent to those skilled in the art in light of the foregoingdescription. Accordingly, the invention is intended to embrace all ofthe alternatives and variations that fall within the spirit and scope ofthe appended claims.

We claim:
 1. Process for the preparation of products of formula:##STR25## in which: R represents a hydrogen atom or an acetyl radical,R₁represents a benzoyl radical or a radical R₂ --O--CO-- in which R₂represents an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,bicycloalkyl, phenyl or heterocyclyl radical, and Het represents anoptionally substituted aromatic heterocyclyl radical having 5 membersand containing at least one heteroatom, which are identical ordifferent, selected from nitrogen, oxygen and sulphur, comprisingtreating a product of formula: ##STR26## in which Het and R₁ are definedas above, G₁ represents a protective group of the hydroxyl functionalgroup, G₂ represents an acetyl radical or a protective group of thehydroxyl functional group, R₃ represents a hydrogen atom or an alkoxyradical or an optionally substituted aryl radical and R₄ represents ahydrogen atom, in acid medium to produce a product of formula: ##STR27##in which Het and R₁ are defined as above, G'₁ represents a hydrogen atomor a protective group of the hydroxyl functional group and G'₂represents a hydrogen atom or an acetyl radical or a protective group ofthe hydroxyl functional group, and then, optionally, the G'₁ and G'₂protective groups are replaced by hydrogen atoms and the product thusobtained is isolated.
 2. Process for the preparation according to claim1 of products for whichR represents a hydrogen atom or an acetylradical, R₁ represents a benzoyl radical or a radical R₂ --O--CO inwhich R₂ represents:a straight or branched alkyl radical containing 1 to8 carbon atoms, an alkenyl radical containing 2 to 8 carbon atoms, analkynyl radical containing 3 to 8 carbon atoms, a cycloalkyl radicalcontaining 3 to 6 carbon atoms, a cycloalkenyl radical containing 4 to 6carbon atoms or a bicycloalkyl radical containing 7 to 10 carbon atoms,these radicals optionally being substituted by at least one substituent,which are identical or different, selected from the halogen atoms andthe hydroxyl radical, alkoxy radical containing 1 to 4 carbon atoms,dialkylamino radical, each alkyl part of which contains 1 to 4 carbonatoms, piperidino radical, morpholino radical, 1-piperazinyl radical(optionally substituted in the 4-position by an alkyl radical containing1 to 4 carbon atoms or by a phenylalkyl radical, the alkyl part of whichcontains 1 to 4 carbon atoms), cycloalkyl radical containing 3 to 6carbon atoms, cycloalkenyl radical containing 4 to 6 carbon atoms,phenyl radical, cyano radical, nitro radical, carboxyl radical oralkoxycarbonyl radical, the alkyl part of which contains 1 to 4 carbonatoms, or a phenyl radical, optionally substituted by at least oneradical, which are identical or different, selected from the alkylradicals containing 1 to 4 carbon atoms or the alkoxy radicalscontaining 1 to 4 carbon atoms, or a saturated or unsaturatednitrogen-containing heterocyclyl radical containing 5 or 6 members,optionally substituted by at least one alkyl radical containing 1 to 4carbon atoms, the cycloalkyl, cycloalkenyl or bicycloalkyl radicals mayoptionally be substituted by at least one alkyl radical containing 1 to4 carbon atoms, and Het represents an aromatic heterocyclic radicalhaving 5 members and containing at least one atom, which are identicalor different, selected from the nitrogen, oxygen or sulphur atoms, suchas thiophene, thiazole, furan, pyrrole, imidazole, isoxazole orpyrazole, optionally substituted by at least one substituent, which areidentical or different, selected from the halogen atoms includingfluorine and chlorine and the alkyl, containing 1 to 4 carbon atoms,aryl, containing 6 to 10 carbon atoms, alkoxy, containing 1 to 4 carbonatoms, aryloxy, containing 6 to 10 carbon atoms, amino, alkylamino,containing 1 to 4 carbon atoms, dialkylamino, each alkyl part of whichcontains 1 to 4 carbon atoms, acylamino, the acyl part of which contains1 to 4 carbon atoms, alkoxycarbonylamino, containing 1 to 4 carbonatoms, acyl, containing 1 to 4 carbon atoms, arylcarbonyl, the aryl partof which contains 6 to 10 carbon atoms, cyano, nitro, hydroxyl,carboxyl, carbamoyl, alkylcarbamoyl, the alkyl part of which contains 1to 4 carbon atoms, dialkylcarbamoyl, each alkyl part of which contains 1to 4 carbon atoms, or alkoxycarbonyl, the alkoxy part of which contains1 to 4 carbon atoms, radicals.
 3. Process for the preparation accordingto claim 1 of products of which R represents a hydrogen atom or anacetyl radical, R₁ represents a benzoyl radical or a radical R₂--O--CO-- in which R₂ represents a t-butyl radical and Het represents a2- or 3-thienyl or 2-or 3-furyl radical.
 4. Process according to claim1, wherein the acid treatment is carried out by means of an inorganic ororganic acid in an organic solvent at a temperature between -10° and 60°C.
 5. Process according to claim 4, wherein the acid is selected fromhydrochloric, sulphuric, acetic, methanesulphonic,trifluoromethanesulphonic and p-toluenesulphonic acids, used alone or asa mixture.
 6. Process according to claim 4, wherein the solvent isselected from alcohols, ethers, esters, halogenated aliphatichydrocarbons, aromatic hydrocarbons and nitriles.
 7. Process accordingto claim 1, wherein the protective groups of the hydroxyl functionalgroups are selected from the 2,2,2-trichloroethoxycarbonyl,2-(2-(trichloromethyl)propoxy)carbonyl, trialkylsilyl, dialkylarylsilyl,alkyldiarylsilyl and triarylsilyl radicals in which the alkyl radicalscontain 1 to 4 carbon atoms and the aryl radicals are phenyl radicals.8. Process according to claim 7, wherein, when G₁ and/or G₂ represent asilylated radical, their replacement by hydrogen atoms is carried outsimultaneously with the replacement of the protective group of the sidechain by treatment in acid medium.
 9. Process according to claim 7,wherein, when G'₁ and/or G'₂ represent a 2,2,2-trichloroethoxycarbonylor 2-(2-(trichloromethyl)propoxy)carbonyl radical, their replacement bya hydrogen atom is carried out with zinc, optionally in combination withcopper, in the presence of acetic acid at a temperature between 20° and60° C. or else by means of an inorganic or organic acid in solution inan aliphatic alcohol or in an aliphatic ester in the presence of zinc,optionally in combination with copper.
 10. Process according to one ofclaim 1, wherein a product of formula: ##STR28## in which Het and R₁ aredefined as in one of claims 1, 2 or 3, G₁ represents a protective groupof the hydroxyl functional group, G₂ represents an acetyl radical or aprotective group of the hydroxyl functional group, R₃ and R₄, which areidentical or different, represent an alkyl radical containing 1 to 4carbon atoms or an aralkyl radical, the alkyl part of which contains 1to 4 carbon atoms, or an aryl radical, or else R₃ represents atrihalomethyl radical or a phenyl radical substituted by a trihalomethylradical and R₄ represents a hydrogen atom, or else R₃ and R₄ form,together with the carbon atom to which they are bonded, a ring having 4to 7 members, is treated in acid medium to produce a product of formula:##STR29## in which Het is defined as in one of claims 1, 2 or 3, G'₁represents a hydrogen atom or a protective group of the hydroxylfunctional group and G'₂ represents an acetyl radical or a protectivegroup of the hydroxyl functional group, which is acylated by means ofbenzoyl chloride or of a reactive derivative of formula:

    R.sub.2 --O--CO--X

in which R₂ is defined as in one of claims 1, 2 or 3 and X represents ahalogen atom or an --O--R₂ or --O--CO--O--R₂ residue, to produce aproduct of formula: ##STR30## in which Het, R₁, G'₁ and G'₂ are definedas above, the G'₁ and G'₂ protective groups are then replaced, ifnecessary, by hydrogen atoms, and the product obtained is isolated. 11.Process according to claim 10, wherein the acid treatment is carried outby means of an inorganic or organic acid in an organic solvent at atemperature between -10° and 60° C.
 12. Process according to claim 11,wherein the acid is selected from hydrochloric, sulphuric, acetic,methanesulphonic, trifluoromethanesulphonic, p-toluenesulphonic andformic acids, used alone or as a mixture.
 13. Process according to claim11, wherein the solvent is selected from alcohols, ethers, esters,halogenated aliphatic hydrocarbons, aromatic hydrocarbons and nitriles.14. Process according to claim 10, wherein the acylation is carried outin an inert organic solvent in the presence of an inorganic or organicbase.
 15. Process according to claim 14, wherein the inert organicsolvent is selected from esters and halogenated aliphatic hydrocarbons.16. Process according to claim 13, wherein the reaction is carried outat a temperature between 0° and 50° C.
 17. Process according to claim10, wherein the replacement by hydrogen atoms of the G'₁ and optionallyG'₂ protective groups, when they represent a2,2,2-trichloroethoxycarbonyl or 2-(2-(trichloromethyl)propoxy)carbonylradical, is carried out with zinc, optionally in combination withcopper, in the presence of acetic acid at a temperature between 30° and60° C. or by means of an inorganic or organic acid in solution in analiphatic alcohol containing 1 to 3 carbon atoms or in an aliphaticester in the presence of zinc, optionally in combination with copper.18. Process for the preparation of a product of formula: ##STR31## inwhich: R represents a hydrogen atom or an acetyl radical,R₁ represents abenzoyl radical or a radical R₂ --O--CO-- in which R₂ represents analkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, phenylor heterocyclyl radical, and Het represents an optionally substitutedaromatic heterocyclyl radical having 5 members and containing at leastone identical or different heteroatom selected from nitrogen, oxygen andsulphur,comprising esterifying protected 10 -deacetylbaccatin III orbaccatin III of formula: ##STR32## in which G₁ represents a protectivegroup of the hydroxyl functional group and G₂ represents an acetylradical or a protective group of the hydroxyl functional group, by meansof an acid of formula: ##STR33## in which Het and R₁ are defined as inclaim 1, and G₃ represents a protective group of the hydroxyl functionalgroup, or of an activated derivative of this acid, to produce a productof formula: ##STR34## in which Het, R₁, G₁, G₂ and G₃ are defined asabove, the G₁, G₂ and G₃ protective groups of which are replaced byhydrogen atoms, and the product obtained is isolated.
 19. Process forthe preparation according to claim 18 of products whereinR represents ahydrogen atom or an acetyl radical, R₁ represents a benzoyl radical or aradical R₂ --O--CO in which R₂ represents:a straight or branched alkylradical containing 1 to 8 carbon atoms, an alkenyl radical containing 2to 8 carbon atoms, an alkynyl radical containing 3 to 8 carbon atoms, acycloalkyl radical containing 3 to 6 carbon atoms, a cycloalkenylradical containing 4 to 6 carbon atoms or a bicycloalkyl radicalcontaining 7 to 10 carbon atoms, these radicals optionally beingsubstituted by at least one substituent, which are identical ordifferent, selected from the halogen atoms and the hydroxyl radical,alkoxy radical containing 1 to 4 carbon atoms, dialkylamino radical,each alkyl part of which contains 1 to 4 carbon atoms, piperidinoradical, morpholino radical, 1-piperazinyl radical (optionallysubstituted in the 4-position by an alkyl radical containing 1 to 4carbon atoms or by a phenylalkyl radical, the alkyl part of whichcontains 1 to 4 carbon atoms), cycloalkyl radical containing 3 to 6carbon atoms, cycloalkenyl radical containing 4 to 6 carbon atoms,phenyl radical, cyano radical, nitro radical, carboxyl radical oralkoxycarbonyl radical, the alkyl part of which contains 1 to 4 carbonatoms, or a phenyl radical, optionally substituted by at least oneradical, which are identical or different, selected from the alkylradicals containing 1 to 4 carbon atoms or the alkoxy radicalscontaining 1 to 4 carbon atoms, or a saturated or unsaturatednitrogen-containing heterocyclyl radical containing 5 or 6 members,optionally substituted by at least one alkyl radical containing 1 to 4carbon atoms, the cycloalkyl, cycloalkenyl or bicycloalkyl radicalsoptionally be substituted by at least one alkyl radical containing 1 to4 carbon atoms, and Het represents an aromatic heterocyclic radicalhaving 5 members and containing at least one atom, which are identicalor different, selected from the nitrogen, oxygen or sulphur atoms,including thiophene, thiazole, furan, pyrrole, imidazole, isoxazole orpyrazole, optionally substituted by at least one substituent, which areidentical or different, selected from the halogen atoms includingfluorine and chlorine and the alkyl, containing 1 to 4 carbon atoms,aryl, containing 6 to 10 carbon atoms, alkoxy, containing 1 to 4 carbonatoms, aryloxy, containing 6 to 10 carbon atoms, amino, alkylamino,containing 1 to 4 carbon atoms, dialkylamino, each alkyl part of whichcontains 1 to 4 carbon atoms, acylamino, the acyl part of which contains1 to 4 carbon atoms, alkoxycarbonylamino, containing 1 to 4 carbonatoms, acyl, containing 1 to 4 carbon atoms, arylcarbonyl, the aryl partof which contains 6 to 10 carbon atoms, cyano, nitro, hydroxyl,carboxyl, carbamoyl, alkylcarbamoyl, the alkyl part of which contains 1to 4 carbon atoms, dialkylcarbamoyl, each alkyl part of which contains 1to 4 carbon atoms, or alkoxycarbonyl, the alkoxy part of which contains1 to 4 carbon atoms, radicals.
 20. Process for the preparation accordingto claim 18 of products wherein R represents a hydrogen atom or anacetyl radical, R₁ represents a benzoyl radical or a radical R₂--O--CO-- in which R₂ represents a t-butyl radical and Het represents a3-thienyl or 3-furyl radical.
 21. Process according to claim 18, whereinthe esterification is carried out by means of free acid, the reactionbeing carried out in the presence of a condensation agent selected fromcarbodiimides and reactive carbonates and of an activating agentselected from aminopyridines in an organic solvent selected from ethers,ketones, esters, nitriles, aliphatic hydrocarbons, halogenated aliphatichydrocarbons and aromatic hydrocarbons at a temperature between --10°and 90° C.
 22. Process according to claim 18, wherein the esterificationby means of the anhydride is carried out in the presence of anactivating agent selected from aminopyridines in an organic solventselected from ethers, esters, ketones, nitriles, aliphatic hydrocarbons,halogenated aliphatic hydrocarbons and aromatic hydrocarbons at atemperature between 0° and 90° C.
 23. Process according to claim 18,wherein the esterification is carried out by means of a halide or of ananhydride with an aliphatic or aromatic acid, optionally prepared insitu, the reaction being carried out in the presence of a base selectedfrom tertiary aliphatic amines in an organic solvent selected fromethers, esters, ketones, nitriles, aliphatic hydrocarbons, halogenatedaliphatic hydrocarbons and aromatic hydrocarbons at a temperaturebetween 0° and 80° C.
 24. Process according to claim 18, wherein thereplacement of the G₁, G₂ and G₃ protective groups by hydrogen atoms iscarried out by treatment With zinc, optionally in combination withcopper, in the presence of acetic acid at a temperature between 30° and60° C. or by means of an inorganic or organic acid such as hydrochloricacid or acetic acid in solution in an aliphatic alcohol containing 1 to3 carbon atoms or an aliphatic ester such as ethyl acetate, isopropylacetate or n-butyl acetate in the presence of zinc, optionally incombination with some copper, when G₁, G₂ and/or G₃ represent a2,2,2-trichloroethoxycarbonyl or 2-(2(trichloromethyl)propoxy)carbonylradical, or by treatment in acid medium such as for example hydrochloricacid in solution in an aliphatic alcohol containing 1 to 3 carbon atomsincluding methanol, ethanol, propanol and isopropanol or aqueoushydrofluoric acid at a temperature between 0° and 40° C. when G₁, G₂and/or G₃ represent a silylated radical.
 25. Process according to claim18, characterized in that, when G₃ represents a --CH₂ --Ph radical, thereplacement is first carried out of the G₁ and G₂ groups by hydrogenatoms under the conditions of claim 24 before replacing the G₃ group byhydrogenolysis.